RT Journal Article SR Electronic T1 Cross-reactivity of Ryanodine Receptors with Plasma Membrane Ion Channel Modulators JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP mol.111.071167 DO 10.1124/mol.111.071167 A1 Jake T Neumann A1 Julio A Copello YR 2011 UL http://molpharm.aspetjournals.org/content/early/2011/06/10/mol.111.071167.abstract AB Various pharmacological agents designed to modulate plasma membrane ion channels appear to significantly affect intracellular Ca2+ signaling when acting on their target receptor. Some agents could also cross-react (modulate channels or receptors beyond their putative target) with intracellular Ca2+ transporters. This paper investigated the potential of thirty putative modulators of either plasma membrane K+, Na+ or transient receptor potential (TRP) channels to cross-react with intracellular Ca2+ release channels [i.e., ryanodine receptors (RyRs)] from skeletal muscle sarcoplasmic reticulum (SR). Screening for cross-reactivity of these various agents was performed by measuring the rate of spontaneous Ca2+ leak or caffeine-induced Ca2+ release from SR microsomes. Four of the agents displayed a strong cross-reactivity and were further evaluated with skeletal RyR (RyR1) reconstituted into planar bilayers. UCL 1684 (K+ channel antagonist) and lamotrigine (Na+ channel antagonist) were found to significantly inhibit the RyR1-mediated caffeine-induced Ca2+ release. TRP channel agonists anandamide and (-)menthol were found to inhibit and activate RyR1, respectively. High concentrations of nine other agents produced partial inhibition of RyR1-mediated Ca2+ release from SR microsomes. Various pharmacological agents, especially TRP modulators, also inhibited a minor RyR1-independent component of the SR Ca2+ leak. Overall, ~43% of the agents selected cross-reacted with RyR1-mediated and/or RyR1-independent Ca2+ leak from intracellular stores.Thus, cross-reactivity should be considered when using pharmacological agents to determine the role of plasmalemma channels in Ca2+ homeostasis.